- Analogues of the potent nonpolyglutamatable antifolate N(α)-(4-amino-4- deoxypteroyl)-N(δ)-hemiphthaloyl-L-ornithine (PT523) with modifications in the side chain, p-aminobenzoyl moiety, or 9,10-bridge: Synthesis and in vitro antitumor activity
-
Seven N(α)-(4-amino-4-deoxypteroyl)-N(δ)-hemiphthaloyl-L-ornithine (2, PT523) analogues were synthesized by modifications of the literature synthesis of the corresponding AMT (1) analogues and were tested as inhibitors of tumor cell growth. In growth assa
- Rosowsky, Andre,Wright, Joel E.,Vaidya, Chitra M.,Forsch, Ronald A.,Bader, Henry
-
p. 1620 - 1634
(2007/10/03)
-
- Synthesis and antifolate evaluation of 10-ethyl-5-methyl-5,10- dideazaaminopterin and an alternative synthesis of 10-ethyl-10- deazaaminopterin (edatrexate)
-
Previous findings suggesting that 5,10-dialkyl-substituted derivatives of 5,10-dideazaaminopterin warranted study as potential antifolates prompted synthesis of 10-ethyl-5-methyl-5,10-dideazaaminopterin (12a). The key step in the synthetic route to 12a was Wittig condensation of the tributylphosphorane derived from 6-(bromomethyl)-2,4-diamino-5-methylpyrido[2,3-d]pyrimidine (7a) with methyl 4-propionylbenzoate. Reaction conditions for the Wittig condensation were developed using the tributylphosphorane prepared from 6- (bromomethyl)-2,4-pteridinediamine (7b) as a model. Each of the respective Wittig products 8a and 8b was obtained in 75-80% yield. Hydrogenation of 8a and 8b at their 9,10-double bond afforded 4-amino-4-deoxy-10-ethyl-5-methyl- 5,10-dideazapteroic acid methyl ester (9a) and 4-amino-4-deoxy-10-ethyl-10- deazapteroic acid methyl ester (9b). This route to 9b intersects reported synthetic approaches leading to 10-ethyl-10-deazaaminopterin (10-EDAM, edatrexate), an agent now in advanced clinical trials. Thus the Wittig approach affords an alternative synthetic route to 10-EDAM. Remaining steps were ester hydrolysis of 9a,b to give carboxylic acids 10a,b followed by standard peptide coupling with diethyl L-glutamate to produce diethyl esters 11a,b, which on hydrolysis gave 12a and 10-EDAM (12b), respectively. The relative influx of 12a was enhanced about 3.2-fold over MTX, but as an inhibitor of dihydrofolate reductase (DHFR) from L1210 cells and in the inhibition of L1210 cell growth in vitro, this compound was approximately 20- fold less effective than MTX (DHFR inhibition, K(i) = 4.82 ± 0.60 pM for MTX, 100 pM for 12a; cell growth, IC50 = 3.4 ± 1.0 nM for MTX, 65 ± 18 nM for 12a).
- Piper,Johnson,Otter,Sirotnak
-
p. 3002 - 3006
(2007/10/02)
-